Affiliation:
1. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
2. Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
3. Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY
4. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
5. Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA
6. Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY
7. Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumor progression. We identified sterol O-acyltransferase 1 (SOAT1) as a key player in sustaining the mevalonate pathway by converting cholesterol to inert cholesterol esters, thereby preventing the negative feedback elicited by unesterified cholesterol. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo and reveals a mevalonate pathway dependency in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH). In contrast, pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss, indicating a potential therapeutic window for inhibiting SOAT1 in PDAC.
Funder
Cold Spring Harbor Laboratory
National Institutes of Health
Lustgarten Foundation
Thompson Foundation
Northwell Health Affiliation
Northwell Health Tissue Donation Program
Cold Spring Harbor Laboratory Association
Simons Foundation
Howard Hughes Medical Institute
Pershing Square Sohn Cancer Research Alliance
National Cancer Institute
Thompson Family Foundation
Pancreatic Cancer Action Network
American Association for Cancer Research
Simons Center for Quantitative Biology
Human Frontier Science Program
European Molecular Biology Organization
State of New York
American-Italian Cancer Foundation
Memorial Sloan Kettering Cancer Center
TCGA Research Network
National Human Genome Research Institute
National Heart, Lung, and Blood Institute
National Institute on Drug Abuse
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke
Publisher
Rockefeller University Press
Subject
Immunology,Immunology and Allergy